Abstract
The objective of the study was to investigate the pharmacokinetic drug-drug interactions between tacrolimus (TAC) and mycophenolate mofetil (MMF) in healthy Korean male volunteers. Seventeen volunteers participated in a three-period, single-dose, and fixed sequence study. They sequentially received MMF, TAC, and the combination. Concentrations of TAC, mycophenolic acid (MPA), and its metabolites MPA 7-O-glucuronide and MPA acyl glucuronide were measured. The variants of CYP3A4, CYP3A5, SLCO1B1, SLCO1B3, ABCC2, UGT1A9, and UGT2B7 were genotyped. Drug interaction was evaluated with a non-compartmental analysis and population pharmacokinetic modelling to quantify the interaction effect. A total of 1,082 concentrations of those analytes were analysed. AUC0-inf of TAC increased by 22.1% (322.4 ± 174.1 to 393.6 ± 121.7 ng·h/mL; P < 0.05) when co-administered with MMF, whereas the pharmacokinetic parameters of MPA and its metabolites were not changed by TAC. Apparent clearance (CL/F) of TAC was 17.8 L/h [relative standard error (RSE) 11%] or 13.8 L/h (RSE 11%) without or with MMF, respectively. Interaction was explained by the exponential model. The CYP3A5 genotype was the only significant covariate. The population estimate of CL/F of TAC was 1.48-fold (RSE 16%) in CYP3A5 expressers when compared to nonexpressers. CL/F of TAC was decreased when co-administered with MMF in these subjects.
Highlights
CL/F was calculated from dose and AUC0-inf; tmax is presented as median; P value was obtained by paired t-test or signed rank test
The cytochrome P450 3A5 (CYP3A5) genotype markedly influences the pharmacokinetics of TAC, while uridine glucuronosyl transferase (UGT) and solute carrier organic anion transporter (SLCO) genotypes have been related with significantly increased dose-adjusted mycophenolic acid (MPA) trough levels[16,17,18]
We evaluated the pharmacokinetic interactions between TAC and mycophenolate mofetil (MMF) in healthy volunteers using the non-linear mixed effect model
Summary
CL/F was calculated from dose and AUC0-inf; tmax is presented as median (min-max); P value was obtained by paired t-test or signed rank test. There is a lack of evidence for drug interaction in terms of pharmacokinetic parameters. The possible drug interaction between TAC and MMF and factors related to the effect of interaction have never been investigated in human subjects. A new study is needed to investigate the pharmacokinetic interaction by comparing pharmacokinetic parameters between monotherapy and combination administration. To find the factors that contribute to pharmacokinetic interaction between TAC and MMF, population pharmacokinetic modelling is useful. Evaluation of the influence of drug interactions on the pharmacokinetic changes enables fine dose adjustment in patients treated with TAC and MMF. The purpose of this study was to investigate the interaction between TAC and MMF in healthy volunteers using linear and nonlinear models. We planned to assess the magnitude of pharmacokinetic interaction by clinical covariates or genotypes
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